Oncogenic EP300 can be targeted with inhibitors of aldo-keto reductases

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Title: Oncogenic EP300 can be targeted with inhibitors of aldo-keto reductases
Authors: Mahmud, Z
Asaduzzaman, M
Kumar, U
Masrour, N
Jugov, R
Coombes, RC
Shousha, S
Hu, Y
Lam, EW-F
Yagüe, E
Item Type: Journal Article
Abstract: E-cadherin transcriptional activator EP300 is down-regulated in metaplastic breast carcinoma, a rare form of triple negative and E-cadherin-negative aggressive breast cancer with a poor clinical outcome. In order to shed light on the regulation of E-cadherin by EP300 in breast cancer we analyzed by immunohistochemistry 41 cases of invasive breast cancer with both E-cadherinhigh and E-cadherinlow expression levels, together with 20 non-malignant breast tissues. EP300 and E-cadherin showed a positive correlation in both non-malignant and cancer cases and both markers together were better predictors of lymph node metastasis than E-cadherin alone. These data support a metastasis suppressor role for EP300 in breast cancer. However, some reports suggest an oncogenic role for EP300. We generated a breast cancer cell model to study E-cadherin-independent effects of EP300 by over-expression of EP300 in HS578T cells which have E-cadherin promoter hypermethylated. In this cell system, EP300 led to up-regulation of mesenchymal (vimentin, Snail, Slug, Zeb1) and stemness (ALDH+ and CD44high/CD24low) markers, increases in migration, invasion, anchorage-independent growth and drug resistance. Genome-wide expression profiling identified aldo-keto reductases AKR1C1-3 as effectors of stemness and drug resistance, since their pharmacological inhibition with flufenamic acid restored both doxorubicin and paclitaxel sensitivity and diminished mammosphere formation. Thus, in cells with a permissive E-cadherin promoter, EP300 acts as a tumour/metastasis supressor by up-regulating E-cadherin expression, maintenance of the epithelial phenotype and avoidance of an epithelial-to-mesenchymal transition. In cells in which the E-cadherin promoter is hypermethylated, EP300 functions as an oncogene via up-regulation of aldo-keto reductases. This offers the rationale of using current aldo-keto reductase inhibitors in breast cancer treatment.
Issue Date: 1-May-2019
Date of Acceptance: 7-Mar-2019
URI: http://hdl.handle.net/10044/1/69160
DOI: https://dx.doi.org/10.1016/j.bcp.2019.03.009
ISSN: 0006-2952
Publisher: Elsevier
Start Page: 391
End Page: 403
Journal / Book Title: Biochemical Pharmacology
Volume: 163
Copyright Statement: © 2019 Elsevier Ltd. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor/Funder: Cancer Research UK
Breast Cancer Now
Medical Research Council (MRC)
Breast Cancer Now
Commonwealth Scholarship Commission
Funder's Grant Number: C37/A12011
2012MayPR070
MR/N012097/1
2014NovPhD326
BDCS-2017-61
Keywords: Aldo-keto reductase
Breast cancer
E-cadherin
EP300
Epidermal-to-mesenchymal transition
Lymph node metastasis
1115 Pharmacology and Pharmaceutical Sciences
Pharmacology & Pharmacy
Publication Status: Published
Conference Place: England
Embargo Date: 2020-03-09
Online Publication Date: 2019-03-09
Appears in Collections:Division of Surgery
Division of Cancer
Department of Medicine
Faculty of Medicine



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